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Cells. 2016 Apr 25;5(2). pii: E21. doi: 10.3390/cells5020021.

A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy.

Author information

1
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. galant.damien@gmail.com.
2
Inserm U1062/Inra1260, Aix-Marseille Université, Marseille 13385, France. benedicte.gaborit@ap-hm.fr.
3
APHM, Endocrinology, Metabolic Diseases and Nutrition, Marseille 13385, France. benedicte.gaborit@ap-hm.fr.
4
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. camille.desgrouas@univ-amu.fr.
5
Laboratoire de Chimie Analytique, Faculté de Pharmacie, Aix-Marseille Université, Marseille 13385, France. camille.desgrouas@univ-amu.fr.
6
Inserm U1062/Inra1260, Aix-Marseille Université, Marseille 13385, France. inesabdesselam@hotmail.com.
7
CNRS, CRMBM UMR 7339, Aix-Marseille Université, Marseille 13385, France. inesabdesselam@hotmail.com.
8
CNRS, CRMBM UMR 7339, Aix-Marseille Université, Marseille 13385, France. monique.bernard@univ-amu.fr.
9
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. nicolas.levy@univ-amu.fr.
10
APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille 13385, France. nicolas.levy@univ-amu.fr.
11
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. francoise.merono@univ-amu.fr.
12
Institut de Myologie, UMR_S U974 INSERM-UPMC-CNRS-AIM, Paris 75013, France. c.coirault@institut-myologie.org.
13
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. patrice.roll@univ-amu.fr.
14
APHM, CHU de la Timone, Laboratoire de Biologie Cellulaire, Marseille 13385, France. patrice.roll@univ-amu.fr.
15
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. arnaud.lagarde@ap-hm.fr.
16
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. Nathalie.BONELLO@ap-hm.fr.
17
APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille 13385, France. Nathalie.BONELLO@ap-hm.fr.
18
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. Patrice.BOURGEOIS@ap-hm.fr.
19
APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille 13385, France. Patrice.BOURGEOIS@ap-hm.fr.
20
Inserm U1062/Inra1260, Aix-Marseille Université, Marseille 13385, France. anne.dutour@ap-hm.fr.
21
APHM, Endocrinology, Metabolic Diseases and Nutrition, Marseille 13385, France. anne.dutour@ap-hm.fr.
22
Inserm UMR_S U910, Faculté de Médecine, Aix-Marseille Université, Marseille 13385, France. catherine.badens@univ-amu.fr.
23
APHM, CHU de la Timone, Laboratoire de Génétique Moléculaire, Marseille 13385, France. catherine.badens@univ-amu.fr.

Abstract

ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral Dysplasia (MAD). We report here the phenotype of a patient referred for severe metabolic syndrome and cardiomyopathy, carrying a mutation in ZMPSTE24. The patient presented with a partial lipodystrophic syndrome associating hypertriglyceridemia, early onset type 2 diabetes, and android obesity with truncal and abdominal fat accumulation but without subcutaneous lipoatrophy. Other clinical features included acanthosis nigricans, liver steatosis, dilated cardiomyopathy, and high myocardial and hepatic triglycerides content. Mutated fibroblasts from the patient showed increased nuclear shape abnormalities and premature senescence as demonstrated by a decreased Population Doubling Level, an increased beta-galactosidase activity and a decreased BrdU incorporation rate. Reduced prelamin A expression by siRNA targeted toward LMNA transcripts resulted in decreased nuclear anomalies. We show here that a central obesity without subcutaneous lipoatrophy is associated with a laminopathy due to a heterozygous missense mutation in ZMPSTE24. Given the high prevalence of metabolic syndrome and android obesity in the general population, and in the absence of familial study, the causative link between mutation and phenotype cannot be formally established. Nevertheless, altered lamina architecture observed in mutated fibroblasts are responsible for premature cellular senescence and could contribute to the phenotype observed in this patient.

KEYWORDS:

ZMPSTE24; cardiomyopathy; laminopathy; metabolic syndrome; nuclear anomalies; premature senescence

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